TWI447097B - 胺基酸衍生物 - Google Patents
胺基酸衍生物 Download PDFInfo
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- TWI447097B TWI447097B TW098131323A TW98131323A TWI447097B TW I447097 B TWI447097 B TW I447097B TW 098131323 A TW098131323 A TW 098131323A TW 98131323 A TW98131323 A TW 98131323A TW I447097 B TWI447097 B TW I447097B
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- TW
- Taiwan
- Prior art keywords
- group
- compound
- propenyl
- hydrate
- pharmaceutically acceptable
- Prior art date
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- 150000003862 amino acid derivatives Chemical class 0.000 title claims description 35
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 186
- 229960004799 tryptophan Drugs 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 26
- 230000000202 analgesic effect Effects 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- 125000003282 alkyl amino group Chemical group 0.000 claims 2
- 125000005577 anthracene group Chemical group 0.000 claims 1
- 125000005597 hydrazone group Chemical group 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 324
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 213
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 201
- 238000004519 manufacturing process Methods 0.000 description 173
- 239000013078 crystal Substances 0.000 description 103
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 70
- 239000002253 acid Substances 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- 238000012360 testing method Methods 0.000 description 20
- -1 α -[3-(2-fluorophenyl)propenyl]-D-tryptophan Chemical compound 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- 208000002193 Pain Diseases 0.000 description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 230000036407 pain Effects 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- IOUDZAFBPDDAMK-AATRIKPKSA-N (e)-3-(2-fluorophenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=CC=CC=C1F IOUDZAFBPDDAMK-AATRIKPKSA-N 0.000 description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical group C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 11
- 208000004296 neuralgia Diseases 0.000 description 11
- 208000021722 neuropathic pain Diseases 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 235000013985 cinnamic acid Nutrition 0.000 description 10
- 229930016911 cinnamic acid Natural products 0.000 description 10
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 150000001335 aliphatic alkanes Chemical class 0.000 description 9
- 229960004441 tyrosine Drugs 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 235000001671 coumarin Nutrition 0.000 description 8
- 229960000956 coumarin Drugs 0.000 description 8
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 7
- 229940035676 analgesics Drugs 0.000 description 7
- 239000000730 antalgic agent Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 6
- 208000032826 Ring chromosome 3 syndrome Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 235000015165 citric acid Nutrition 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 4
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000028389 Nerve injury Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229960002989 glutamic acid Drugs 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 230000008764 nerve damage Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- JMUOYANNVIFGFN-SNAWJCMRSA-N (e)-3-(2,6-difluorophenyl)prop-2-enoic acid Chemical compound OC(=O)\C=C\C1=C(F)C=CC=C1F JMUOYANNVIFGFN-SNAWJCMRSA-N 0.000 description 3
- PQDXPFJQTKGTFP-UHFFFAOYSA-N 3-(2,4-difluorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC=C(F)C=C1F PQDXPFJQTKGTFP-UHFFFAOYSA-N 0.000 description 3
- XAWHCSKPALFWBI-UHFFFAOYSA-N 3-(2,5-difluorophenyl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=CC(F)=CC=C1F XAWHCSKPALFWBI-UHFFFAOYSA-N 0.000 description 3
- XWGDODCEQXQAFQ-UHFFFAOYSA-N 3-(4-phenoxyphenyl)prop-2-enoic acid Chemical compound C1=CC(C=CC(=O)O)=CC=C1OC1=CC=CC=C1 XWGDODCEQXQAFQ-UHFFFAOYSA-N 0.000 description 3
- VFQOFJQVKVEXIY-UHFFFAOYSA-N 3-(phenylmethoxycarbonylamino)-3-piperidin-3-ylpropanoic acid Chemical compound C1CCNCC1C(CC(=O)O)NC(=O)OCC1=CC=CC=C1 VFQOFJQVKVEXIY-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000004454 Hyperalgesia Diseases 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000004395 L-leucine Substances 0.000 description 3
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 3
- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
- 229960003136 leucine Drugs 0.000 description 3
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- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000004044 response Effects 0.000 description 3
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- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- SJWZTDOJWBAUCJ-UHFFFAOYSA-N pyrrolidin-1-yl 3-(2-fluorophenyl)prop-2-enoate Chemical compound FC1=CC=CC=C1C=CC(=O)ON1CCCC1 SJWZTDOJWBAUCJ-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- GUVRBAGPIYLISA-UHFFFAOYSA-N tantalum atom Chemical compound [Ta] GUVRBAGPIYLISA-UHFFFAOYSA-N 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
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- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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Description
本發明係關於胺基酸衍生物與其藥學上容許之鹽及水合物,以及含有該化合物作為有效成分之醫藥。
「疼痛」,根據病因分類時,可大致分為傷害損及身體組織之強刺激(侵害刺激)所引起之侵害接受性疼痛(nociceptive pain)(亦即,一般的「疼痛」),以及起因於中樞神經或末梢神經的損傷或功能異常之疾病性疼痛之神經因性疼痛(神經障礙性疼痛)。該神經因性疼痛除了自發性疼痛外,對於侵害性刺激之疼痛閾值降低而不引起痛覺過敏反應或通常疼痛之觸覺刺激所引起之激烈疼痛(allodynia)的症狀,一旦病理性完成則成為慢性而為非常難治性疼痛。
目前,對於一般「疼痛」,使用非類固醇性鎮痛藥(NSAIDs)、非麻藥性鎮痛藥、麻藥性鎮痛藥等,其治療法幾乎確立。然而,關於神經因性疼痛,現狀為幾乎無可符合使用之鎮痛藥。
本發明者們對於各種疼痛顯示效果之化合物進行致力研究的結果發現,本發明之胺基酸衍生物不僅對於侵害接受性疼痛具有優異鎮痛作用,於神經因性疼痛模式動物中亦具有優異鎮痛作用。胺基酸衍生物雖已揭示具有抗過敏作用之化合物中間體N-肉桂醯基色胺酸(非專利文獻1)、抑制非洲蝸牛的巨大神經細胞興奮性之N-肉桂醯基-L-色胺酸、N-肉桂醯基-D-色胺酸、N-3-氯肉桂醯基色胺酸(非專利文獻2)、來自咖啡豆之單離物質之對-香豆醯基-L-色胺酸、咖啡醯基-色胺酸(非專利文獻3)、共聚物單體之N-丙烯醯基-L-色胺酸、N-丙烯醯基-L-白胺酸(非專利文獻4),但任一文獻中均未揭示該等化合物有用於作為醫藥,特別是未記載有用於作為鎮痛藥。再者,專利文獻1中,雖揭示由植物萃取之對-香豆醯基-L-色胺酸、N-咖啡醯基-L-色胺酸、對-香豆醯基-L-酪胺酸等,但未揭示該等化合物具有鎮痛作用等。
[專利文獻1]國際公開WO 2008/009655號公報
[非專利文獻1]「Biomedical Problems」,第58卷,9-38頁(1999年)
[非專利文獻2]「Comparative Biochemistry and Physiology」,第75卷,329-335頁(1983年)
[非專利文獻3]「Bioscience,Biotechnology and Biochemistry」,第59卷,第10號,1887-1890頁(1995年)
[非專利文獻4]「Journal of Polymer Science:Polymer Chemistry Edition」,第10卷,3569-3576頁(1972年)
本發明之目的係提供有用於作為鎮痛藥等之胺基酸衍生物。
本發明者們對於對各種疼痛顯示效果之化合物進行致力研究的結果發現,下述構造式(I’)表示之胺基酸衍生物,於侵害接受性疼痛模式動物與神經因性疼痛模式動物中具有優異鎮痛作用,有用於作為鎮痛藥等醫藥,而完成本發明。
本發明之胺基酸衍生物為不僅對於侵害接受性模式動物顯示優異鎮痛作用,對於神經因性疼痛模式動物亦顯示優異鎮痛作用之新穎化合物,非常有用於作為鎮痛藥等醫藥。
本發明係關於下述通式(I)所示之新穎胺基酸衍生物與其藥學上容許之鹽及水合物。
[式中,R1
表示N位可經甲醯基、苯甲基或碳數1至6之烷基取代之吲哚、經羥基或碳數1至4之烷氧基取代之苯基、可經羧基、胺基、胍基、胺甲醯基或碳數1至4之烷基硫基(alkylsulfanyl)取代之碳數1至6之烷基或羥基,R2
表示氫、碳數1至4之烷基或氰基,R3
表示氫或碳數1至4之烷基,R4
表示氫、碳數1至4之烷基,或可經選自羥基、鹵素、氰基、三氟甲基、苯氧基、碳數1至6之烷基及碳數1至4之烷氧基之1或2個取代基取代之苯基,R5
表示羥基或胺基,又R2
與R4
亦可鍵結形成苯并呋喃環或香豆素環。限制條件為R2
為氫,R4
為經羥基或氯取代之苯基、經羥基與甲氧基取代之苯基、或無取代之苯基時,R1
表示除了無取代之吲哚及羥基苯基以外之取代基;又,R2
為氫,R4
為經甲基取代之苯基時,R1
表示除了經羥基或碳數1至4之烷氧基取代之苯基以外之取代基;又,R2
為氫,R4
為經羥基取代之苯基時,R1
表示除了羧基甲基以外之取代基;又,R2
及R4
為氫時,R1
表示除了無取代之烷基及無取代之吲哚以外之取代基]。
又,本發明係關於含有下述通式(I’)所示之胺基酸衍生物與其藥學上容許之鹽及水合物之至少一種作為有效成分之鎮痛藥等醫藥。
[式中,R1
’表示N位可經甲醯基、苯甲基或碳數1至6之烷基取代之吲哚、經羥基或碳數1至4之烷氧基取代之苯基、可經羧基、胺基、胍基、胺甲醯基或碳數1至4之烷基硫基取代之碳數1至6之烷基或羥基,R2
’表示氫、碳數1至4之烷基或氰基,R3
’表示氫或碳數1至4之烷基,R4
’表示氫、碳數1至4之烷基,或可經選自羥基、鹵素、氰基、三氟甲基、苯氧基、碳數1至6之烷基及碳數1至4之烷氧基之1或2個取代基取代之苯基,R5
’表示羥基或胺基,又R2
’與R4
’亦可鍵結形成苯并呋喃環或香豆素環]。
上述通式(I)及(I’)之取代基中,碳數1至4之烷基較佳表示甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基等直鏈狀或分支狀烷基。碳數1至6之烷基較佳表示甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、新戊基、第三戊基、己基、異己基等直鏈狀或分支狀烷基。碳數1至4之烷氧基較佳表示甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基等直鏈狀或分支狀烷氧基。鹵素表示氟、氯、溴、碘等。另外,R2
與R4
鍵結形成苯并呋喃環或香豆素環時的通式分別以下式[化3]或[化4]表示(R2
’與R4
’鍵結時亦相同)
本發明化合物中,較佳化合物為下述者。
Nα
-丙烯醯基-L-色胺酸[化合物1]
Nα
-[3-(2-羥基苯基)丙烯醯基]-L-色胺酸[化合物2]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-色胺酸[化合物3]
Nα
-[3-(3-氟苯基)丙烯醯基]-L-色胺酸[化合物4]
Nα
-[3-(4-氟苯基)丙烯醯基]-L-色胺酸[化合物5]
Nα
-[3-(3-羥基苯基)丙烯醯基]-L-色胺酸[化合物6]
Nα
-[3-(4-羥基苯基)丙烯醯基]-L-色胺酸[化合物7]
Nα
-(3-苯基丙烯醯基)-L-色胺酸[化合物8]
Nα
-[3-(2-氰基苯基)丙烯醯基]-L-色胺酸[化合物9]
Nα
-[3-(2-三氟甲基苯基)丙烯醯基]-L-色胺酸[化合物10]
Nα
-[3-(2-甲氧基苯基)丙烯醯基]-L-色胺酸[化合物11]
Nα
-[3-(2-氯苯基)丙烯醯基]-L-色胺酸[化合物12]
Nα
-[3-(2,6-二氟苯基)丙烯醯基]-L-色胺酸[化合物13]
Nα
-[3-(2,4-二氟苯基)丙烯醯基]-L-色胺酸[化合物14]
Nα
-[3-(2,5-二氟苯基)丙烯醯基]-L-色胺酸[化合物15]
Nα
-{3-[3,5-雙(三氟甲基)苯基]丙烯醯基}-L-色胺酸[化合物16]
Nα
-[3-(3-氰基苯基)丙烯醯基]-L-色胺酸[化合物17]
Nα
-[3-(4-苯氧基苯基)丙烯醯基]-L-色胺酸[化合物18]
Nα
-[3-(4-氰基苯基)丙烯醯基]-L-色胺酸[化合物19]
Nα
-(苯并呋喃-2-羰基)-L-色胺酸[化合物20]
Nα
-(香豆素環-3-羰基)-L-色胺酸[化合物21]
Nα
-[2-氰基-3-(2-氟苯基)丙烯醯基]-L-色胺酸[化合物22]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-色胺醯胺[化合物23]
Nα
-[3-(2-氟苯基)丙烯醯基]-D-色胺酸[化合物24]
Nα
-(2-氰基-3-苯基丙烯醯基)-L-色胺酸[化合物25]
Nα
-[3-(2-羥基苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物26]
Nα
-[3-(2-氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物27]
Nα
-[3-(4-氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物28]
1-甲基-Nα
-(3-苯基丙烯醯基)-L-色胺酸[化合物29]
Nα
-[3-(2-氰基苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物30]
Nα
-[3-(2,6-二氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物31]
Nα
-[3-(2,4-二氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物32]
Nα
-[3-(2,5-二氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物33]
Nα
-[3-(3-氰基苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物34]
1-甲基-Nα
-[3-(4-苯氧基苯基)丙烯醯基]-L-色胺酸[化合物35]
Nα
-[3-(4-氰基苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物36]
Nα
-[2-氰基-3-(2-氟苯基)丙烯醯基]-1-甲基-L-色胺酸[化合物37]
N-丙烯醯基-O4
-甲基-L-酪胺酸[化合物38]
N-[3-(2-羥基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物39]
N-[3-(2-氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物40]
N-[3-(3-氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物41]
N-[3-(4-氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物42]
N-[3-(3-羥基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物43]
N-[3-(4-羥基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物44]
O4
-甲基-N-(3-苯基丙烯醯基)-L-酪胺酸[化合物45]
N-[3-(2-氰基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物46]
O4
-甲基-N-[3-(2-三氟甲基苯基)丙烯醯基]-L-酪胺酸[化合物47]
N-[3-(2一甲氧基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物48]
N-[3-(2-氯苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物49]
N-[3-(2,6-二氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物50]
N-[3-(2,4-二氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物51]
N-[3-(2,5-二氟苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物52]
N-{3-[3,5-雙(三氟甲基)苯基]丙烯醯基}-O4
-甲基-L-酪胺酸[化合物53]
N-[3-(3-氰基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物54]
O4
-甲基-N-[3-(4-苯氧基苯基丙烯醯基)]-L-酪胺酸[化合物55]
N-[3-(4-氰基苯基)丙烯醯基]-O4
-甲基-L-酪胺酸[化合物56]
N-(苯并呋喃-2-羰基)-O4
-甲基-L-酪胺酸[化合物57]
N-(香豆素環-3-羰基)-O4
-甲基-L-酪胺酸[化合物58]
N-[3-(2-氟苯基)丙烯醯基]-L-白胺酸[化合物60]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-離胺酸鹽酸鹽[化合物61]
N-[3-(2-氟苯基)丙烯醯基]-L-酪胺酸[化合物62]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-鳥胺酸鹽酸鹽[化合物63]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-精胺酸[化合物64]
Nα
-[3-(2-氟苯基)丙烯醯基]-L-麩胺酸[化合物65]
N-[3-(2-氟苯基)丙烯醯基]-L-絲胺酸[化合物66]
N-[3-(2-氟苯基)丙烯醯基]-L-甲硫胺酸[化合物67]
Nα
-[3-(2-氟苯基)丙烯醯基]-1-甲醯基-L-色胺酸[化合物68]
1-乙基-Nα
-[3-(2-氟苯基)丙烯醯基]-L-色胺酸[化合物69]
Nα
-[3-(2-氟苯基)丙烯醯基]-1-異丙基-L-色胺酸[化合物70]
1-正丁基-Nα
-[3-(2-氟苯基)丙烯醯基]-L-色胺酸[化合物71]
1-苯甲基-Nα
-[3-(2-氟苯基)丙烯醯基]-L-色胺酸[化合物72]
Nα
-[3-(2-甲基苯基)丙烯醯基]-L-色胺酸[化合物73]
Nα
-[3-(3-甲基苯基)丙烯醯基]-L-色胺酸[化合物74]
Nα
-[3-(4-甲基苯基)丙烯醯基]-L-色胺酸[化合物75]
Nα
-[3-(4-正丁基苯基)丙烯醯基]-L-色胺酸[化合物76]
Nα
-[3-(4-異丙基苯基)丙烯醯基]-L-色胺酸[化合物77]
Nα
-巴豆醯基-L-色胺酸[化合物78]
Nα
-3-甲基巴豆醯基-L-色胺酸[化合物79]
Nα
-惕各醯基-L-色胺酸[化合物80]
Nα
-反式-2-己烯醯基-L-色胺酸[化合物81]
Nα
-(2-甲基-3-苯基丙烯醯基)-L-色胺酸[化合物82]
又,上述化合物1至82中,化合物1、2、4至11、13、14、38為鈉鹽,化合物60為二鈉鹽,分別於下述實施例中合成。
以下揭示本發明化合物之一般製法。上述通式(I)所示之本發明化合物可根據以下所揭示之(1)或(2)的方法而製造(通式(I’)所示之本發明化合物亦相同)。又,下述雖顯示本發明化合物胺基酸衍生物之L-體的製法,惟以同樣的路徑亦可合成立體異構物之D-體。
(1)R1
為N位可經甲醯基、烷基或苯甲基取代之吲哚、烷氧基苯基、羥基或可經羧基、胺基、胍基或烷基硫基取代之烷基,R2
為氫或烷基,R3
為氫或烷基,R4
為氫、烷基或可經選自羥基、鹵素、氰基、三氟甲基、苯氧基、烷基及烷氧基之1或2個取代基取代之苯基,R5
為羥基,或R2
與R4
鍵結形成苯并呋喃環或香豆素環時,依示於下述[化5]的路徑合成。
通式(A)化合物與通式(B)化合物的反應係於惰性溶媒中,於三乙基胺、N,N-二異丙基乙基胺、嗎啉等有機鹼的存在下,使用適當縮合劑,於室溫下,通常使其反應1小時至24小時,而可製得通式(C)化合物。又,作為惰性溶媒,例如可列舉二氯甲烷、1,2-二氯乙烷、氯仿等鹵化烴系溶媒,四氫呋喃(THF)、1,4-二烷、1,2-二甲氧基乙烷、二乙基醚等醚系溶媒,苯、甲苯。二甲苯等芳香族烴系溶媒等,再者,亦可使用二甲基甲醯胺(DMF)、二甲基亞碸(DMSO)。作為縮合劑,可列舉水溶性碳二亞胺鹽酸鹽(WSC‧HCl)、二環己基碳二亞胺(DCC)、DCC‧HOBt、羰基二咪唑(CDI)等。
通式(C)化合物於甲醇、乙醇、2-丙醇等醇系溶媒中,使用氫氧化鈉、氫氧化鉀、氫氧化鈣等無機鹼的水溶液,進行鹼水解反應,可製得通式(D)化合物。又,R1
有保護基時,以適合條件進行脫保護,可製得通式(D)化合物。例如,保護基為第三丁氧基羰基時,可藉由無機酸處理,又,保護基為2,2,4,6,7-五甲基二氫苯并呋喃-5-磺醯基時,可使用有機酸脫保護。再者,作為無機酸,可列舉氯化氫-二烷、氯化氫-醋酸乙酯等,有機酸可列舉三氟醋酸等。
(2)R1
為可經甲醯基、烷基或苯甲基取代之吲哚、經羥基或烷氧基取代之苯基、或胺甲醯基烷基,R2
為氫,R3
為氫或氰基,R4
為可經選自鹵素或氰基之1或2個取代基取代之苯基,R5
為羥基或胺基時,依示於下述[化6]的路徑合成。
通式(E)化合物的反應係於對反應為惰性之溶媒中,適當縮合劑存在下,使用適當的活性化試劑,於室溫下,通常使其反應1小時至24小時,而可製得活性酯體之通式(F)化合物。通式(F)化合物與通式(G)化合物,於碳酸氫鈉、碳酸氫鉀、碳酸鈉、碳酸鉀等無機鹼的存在下,於惰性溶媒中反應,於室溫下,通常使其反應1小時至30小時,而可製得通式(H)化合物。再者,作為惰性溶媒,例如可列舉二氯甲烷、1,2-二氯乙烷、氯仿等鹵化烴系溶媒,THF、1,4-二烷、1,2-二甲氧基乙烷、二乙基醚等醚系溶媒,苯、甲苯、二甲苯等芳香族烴系溶媒等,亦可使用1,4-二烷-水、THF-DMF之混合溶媒。又,作為縮合劑,可列舉WSC‧HCl、DCC、DCC‧HOBt、CDI等;而作為活性化試劑,可列舉N-羥基琥珀醯亞胺、酚、對-硝基酚等。
上述通式(I)及(I’)所示之化合物,其藥學上容許之鹽存在時,為包含該等各種鹽,例如可列舉與鹽酸、硫酸、硝酸、溴化氫酸、磷酸、過氯酸、硫氰酸、硼酸、甲酸、醋酸、鹵醋酸、丙酸、乙醇酸、檸檬酸、酒石酸、琥珀酸、葡糖酸、乳酸、丙二酸、富馬酸、胺茴酸、安息香酸、桂皮酸、對-甲苯磺酸、萘磺酸、磺胺酸等之酸加成鹽,或者與鈉、鉀等鹼金屬,鈣、鎂等鹼土族金屬或鋁等金屬之鹽,或者與氨、有機胺等鹼類之鹽。該等鹽經由習知方法,可由游離之各化合物而製造,或可互相變換。再者,順式-反式異構物、光學異構物、配位異構物等立體異構物或水合物等溶媒合物或以金屬錯化合物的狀態存在時,本發明亦包含該等任一立體異構物、溶媒合物及錯化合物。
本發明化合物可與適當之醫藥用載體或稀釋劑組合作為醫藥,亦可藉由一般的任何方法製劑化,可製劑化為錠劑、膠囊劑、粉末劑、液劑等經口劑,或可製劑化為皮下、肌肉內、直腸內、鼻腔內投予用之非經口劑。處方的情況中,本發明化合物亦可以其藥學上容許之鹽的形式使用,可單獨或適宜組合使用,又,亦可為與其他醫藥活性成分之調配劑。
本發明化合物之期望投予量,雖根據投予對象、劑型、投予方法、投予期間等而變化,惟為了得到所期望效果,一般而言對於成人,本發明化合物0.5至1000mg可為一日1次至數次經口投予。非經口投予(例如注射劑)時,一日投予量,較佳為前述各投予量之3分之一至10分之一的用量程度。
熔點以YAMATO MP-21型熔點測定器測定,不進行溫度計的校正。核磁共振質譜(1H-NMR)以Bruker ARX-500型核磁共振裝置測定,使用TMS(δ=0)作為內標準物質。矽膠管柱層析係使用BW-127ZH作為順相層析用矽膠,或使用胺基丙基結合型層析矽膠DM1020作為鹼性矽膠(任一者皆為富士Silysia化學公司製)。薄層層析係使用Silica gel F254(Merck,No.5715),使用UV燈及5%磷鉬酸-乙醇呈色試劑檢測。試劑、溶媒類直接使用市售品。
於L-色胺酸甲基酯鹽酸鹽(5.0g)的氯仿(120mL)溶液中,於冰冷下加入三乙基胺(14mL),再加入丙烯酸(1.6mL)。其次,滴下DOC(4.9g)之二氯甲烷(30mL)溶液。於室溫攪拌混合24小時後,於減壓下蒸餾去除一半溶媒,加入丙酮後於冰箱靜置一夜。濾除了三乙基胺鹽酸鹽與DC脲後,於減壓下蒸餾去除濾液的溶媒後所得之殘質油狀物以矽膠管柱層析(BW-127ZH,氯仿:甲醇=19:1)精製,獲得標題化合物(1.5g,28%)呈油狀物。
於L-色胺酸甲基酯鹽酸鹽(7.3g)的二氯甲烷(180mL)懸浮液中,於0℃加入三乙基胺(4.8mL),再加入2-乙醯氧基桂皮酸(7.1g)及WSC‧HCl(6.6g),於室溫攪拌混合20小時。水洗反應混合物後,有機層以無水硫酸鈉乾燥。減壓下蒸餾去除濾液的溶媒後所得之殘質油狀物以矽膠管柱層析(BW-127ZH,氯仿:甲醇=100:1)精製,獲得標題化合物(8.9g,76%)呈晶體。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、3-乙醯氧基桂皮酸(2.9g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.7g,98%)呈非晶形固體。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、4-乙醯氧基桂皮酸(2.9g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.5g,93%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(5.0g)、三乙基胺(2.9mL)、2-氟桂皮酸(3.4g)、WSC‧HCl(3.9g)及二氯甲烷(130mL),與實施例2相同方式製得標題化合物(7.1g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(2.3mL)、3-氟桂皮酸(2.97g)、WSC‧HCl(3.2g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(4.2g,74%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(4.8mL)、4-氟桂皮酸(2.9g)、WSC‧HCl(3.3g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(4.3g,74%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(4.8mL)、桂皮酸(2.6g)、WSC‧HCl(3.3g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(3.7g,67%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(2.0mL)、2-氰基桂皮酸(3.3g)、WSC‧HCl(3.6g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(5.8g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2-三氟甲基桂皮酸(3.1g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(3.4g,70%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(4.8mL)、2-甲氧基桂皮酸(23.1g)、WSC‧HCl(3.3g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(5.2g,88%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2-氯桂皮酸(2.6g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.5g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2,6-二氟桂皮酸(2.6g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(3.9g,85%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2,4-二氟桂皮酸(2.6g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.5g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2,5-二氟桂皮酸(2.6g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.1g,90%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、3,5-雙(三氟甲基)桂皮酸(4.0g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(2.6g,64%)呈晶體。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、4-苯氧基桂皮酸(3.4g)、WSC‧HCl(2.7g,14.1mmol)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(4.9g,94%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(2.2mL)、苯并呋喃-2-羧酸(3.1g)、WSC‧HCl(3.6g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(5.6g,98%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、香豆素環-3-羧酸(2.7g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(2.0g,43%)呈油狀物。
0℃,於甲醇(150mL)滴下亞硫醯氯(16.7mL)後,於室溫加入1-甲基-L-色胺酸(10.0g)。將其直接攪拌混合20小時後,加熱迴流6小時。於減壓下蒸餾去除溶媒所得之殘質中加入二乙基醚,濾取析出之晶體而獲得標題化合物(10.7g,87%)。
由實施例20所獲得之化合物(3.0g)、三乙基胺(1.7mL)、2-乙醯氧基桂皮酸(2.5g)、WSC‧HCl(2.4g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(3.9g,83%)呈油狀物。
由實施例20所獲得之化合物(4.0g)、三乙基胺(2.3mL)、2-氟桂皮酸(2.7g)、WSC‧HCl(3.1g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(3.1g,54%)呈油狀物。
由實施例20所獲得之化合物(2.0g)、三乙基胺(1.1mL)、4-氟桂皮酸(1.4g)、WSC‧HCl(1.6g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(2.7g,94%)呈油狀物。
由實施例20所獲得之化合物(1.4g)、三乙基胺(0.72mL)、2,6-二氟桂皮酸(1.0g)、WSC‧HCl(1.0g)及二氯甲烷(50mL),與實施例2相同方式製得標題化合物(1.1g,51%)呈油狀物。
由實施例20所獲得之化合物(1.0g)、三乙基胺(0.54mL)、2,4-二氟桂皮酸(0.72g)、WSC‧HCl(0.75g)及二氯甲烷(40mL),與實施例2相同方式製得標題化合物(0.73g,49%)呈油狀物。
由實施例20所獲得之化合物(2.0g)、三乙基胺(1.1mL)、2,5-二氟桂皮酸(1.5g)、WSC‧HCl(1.6g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(2.9g,98%)呈油狀物。
由實施例20所獲得之化合物(1.0g)、三乙基胺(0.54mL)、4-苯氧基桂皮酸(0.94g)、WSC‧HCl(0.75g)及二氯甲烷(40mL),與實施例2相同方式製得標題化合物(0.93g,55%)呈油狀物。
碳酸鉀(6.2g)之DMF(50mL)懸浮液中,於0℃滴下Nα
-第三丁氧基羰基-1一甲醯基-L-色胺酸(10.0g)之DMF(70mL)溶液後,於室溫攪拌混合1小時。其次,於0℃滴下碘甲烷(2.8mL)之DMF(25mL)溶液後,於室溫攪拌混合20小時。反應混合物注入至冰水中,以醋酸乙酯萃取。有機層以無水硫酸鈉乾燥後,減壓下蒸餾去除溶媒所得之殘質以矽膠管柱層析(BW-127ZH,正己烷:醋酸乙酯=7:3)精製而製得標題化合物(9.0g,86%)呈晶體。
實施例28所獲得之化合物(8.9g,25.7mmol)之二氯甲烷(200mL)溶液中,於室溫滴下4mol/L氯化氫-二烷(19mL),將其直接攪拌混合15小時。濾取析出之晶體,以二乙基醚洗滌而製得標題化合物(7.2g,99%)。
由實施例29所獲得之化合物(4.0g)、三乙基胺(2.2mL)、2-氟桂皮酸(2.6g)、WSC‧HCl(3.0g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(4.8g,86%)呈油狀物。
由D-色胺酸甲基酯鹽酸鹽(2.5g)、三乙基胺(1.6mL)、2-氟桂皮酸(2.0g)、WSC‧HCl(2.3g)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(3.1g,86%)呈油狀物。
由N-第三丁氧基羰基-L-酪胺酸(50.0g)、碘甲烷(28mL)、碳酸鉀(62.0g)及DMF(500mL),與實施例28相同方式製得標題化合物(50.7g,92%)呈油狀物。
由實施例32所獲得之化合物(50.6g)、4mol/L氯化氫-二烷(123mL)及二氯甲烷(400mL),與實施例29相同方式製得標題化合物(33.7g,84%)呈晶體。
由實施例33所獲得之化合物(3.3g)、丙烯酸(1.1mL)、DCC(3.4g)、三乙基胺(9.5mL,68.2mmol)及氯仿(140mL),與實施例1相同方式製得標題化合物(2.1g,58%)呈晶體。
由實施例33所獲得之化合物(8.0g)、三乙基胺(5.4mL)、2-乙醯氧基桂皮酸(8.1g)、WSC‧HCl(7.5g)及二氯甲烷(200mL),與實施例2相同方式製得標題化合物(8.8g,68%)呈晶體。
由實施例33所獲得之化合物(2.0g)、三乙基胺(1.4mL)、3-乙醯氧基桂皮酸(2.0g)、WSC‧HCl(1.9g)及二氯甲烷(60mL),與實施例2相同方式製得標題化合物(3.1g,96%)呈油狀物。
由實施例33所獲得之化合物(2.0g)、三乙基胺(1.4mL)、4-乙醯氧基桂皮酸(2.0g)、WSC‧HCl(1.9g)及二氯甲烷(60mL),與實施例2相同方式製得標題化合物(2.6g,79%)呈晶體。
由實施例33所獲得之化合物(4.8g)、三乙基胺(3.3mL)、2-氟桂皮酸(3.9g)、WSC‧HCl(4.5g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(6.0g,86%)呈晶體。
由實施例33所獲得之化合物(2.0g)、三乙基胺(1.4mL)、3-氟桂皮酸(1.6g)、WSC‧HCl(1.9g)及二氯甲烷(60mL),與實施例2相同方式製得標題化合物(2.9g,99%)呈油狀物。
由實施例33所獲得之化合物(2.5g)、三乙基胺(3.1mL)、4-氟桂皮酸(1.9g)、WSC‧HCl(2.1g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(2.5g,69%)呈非晶形固體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(53.1mL)、桂皮酸(1.7g)、WSC‧HCl(2.1g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(1.0g,29%)呈油狀物。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2-氰基桂皮酸(2.1g)、WSC‧HCl(72.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(3.2g,86%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2-三氟甲基桂皮酸(2.6g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(4.1g,99%)呈非晶形固體。
由實施例33所獲得之化合物(2.1g)、三乙基胺(3.1mL)、2-甲氧基桂皮酸(2.0g)、WSC‧HCl(2.1g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(2.8g,76%)呈非晶形固體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2-氯桂皮酸(82.2g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(2.9g,76%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2,6-二氟桂皮酸(2.2g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(83.1g,82%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2,4-二氟桂皮酸(2.2g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(3.0g,80%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、2,5-二氟桂皮酸(2.2g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(2.8g,74%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、3,5-雙(三氟甲基)桂皮酸(3.5g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(3.4g,70%)呈油狀物。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、4-苯氧基桂皮酸(2.9g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(3.3g,74%)呈晶體。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、苯并呋喃-2-羧酸(2.0g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(3.4g,96%)呈油狀物。
由實施例33所獲得之化合物(2.5g)、三乙基胺(1.7mL)、香豆素環-3-羧酸(2.3g)、WSC‧HCl(2.3g)及二氯甲烷(70mL),與實施例2相同方式製得標題化合物(2.8g,71%)呈晶體。
由L-白胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.5mL)、2-氟皮酸(3.0g)、WSC‧HCl(3.5g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(4.3g,88%)呈晶體。
由L-絲胺酸甲基酯鹽酸鹽(2.5g)、三乙基胺(2.4mL)、2-氟桂皮酸(2.8g)、WSC‧HCl(3.2g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(4.2g,98%)呈油狀物。
由L-甲硫胺酸甲基酯鹽酸鹽(2.5g)、三乙基胺(2.1mL)、2-氟桂皮酸(2.5g)、WSC‧HCl(2.9g,15.0mmol)及二氯甲烷(80mL),與實施例2相同方式製得標題化合物(3.7g,95%)呈油狀物。
由L-麩胺酸二乙基酯(4.0g)、三乙基胺(5.2mL)、2-氟桂皮酸(3.1g)、WSC‧HCl(3.5g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(4.0g,68%)呈非晶形固體。
由Nα
-第三丁氧基羰基-L-鳥胺酸甲基酯鹽酸鹽(5.0g)、三乙基胺(3.0mL)、2-氟桂皮酸(3.1g)、WSC‧HCl(4.1g)及二氯甲烷(100mL),與實施例2相同方式製得標題化合物(6.9g,99%)呈油狀物。
由Nω
-第三丁氧羰基-L-離胺酸甲基酯鹽酸鹽(10.0g)、三乙基胺(5.6mL)、2-氟桂皮酸(6.7g)、WSC‧HCl(7.7g)及二氯甲烷(200mL),與實施例2相同方式製得標題化合物(10.2g,74%)呈晶體。
由Nω
-(2,2,4,6,7-五甲基二氫苯并呋喃-5-磺醯基)-L-精胺酸甲基酯鹽酸鹽(5.0g)、三乙基胺(1.8mL)、2-氟桂皮酸(2.1g)、WSC‧HCl(2.4g)及二氯甲烷(150mL),與實施例2相同方式製得標題化合物(6.1g,99%)呈非晶形固體。
於實施例1所獲得之化合物(1.0g,3.7mmol)之甲醇(50mL)溶液中,於室溫加入1mol/L之氫氧化鈉水溶液(5.6mL)。將其直接攪拌混合2小時後,於減壓下蒸餾去除溶媒所得之殘質中加入水,以聚苯乙烯結合型對-甲苯磺酸珠粒(2.8mmol/g)(2.0g)調整pH為約7。以Millipore過濾器濾除了珠粒後,濾液於減壓下蒸餾,以二乙基醚濾取析出之晶體而製得標題化合物(0.9g,87%)。
由實施例2所獲得之化合物(5.0g)、1mol/L氫氧化鈉水溶液(37mL)及甲醇(300mL),與實施例60相同方式製得標題化合物(4.3g,94%)呈晶體。
由實施例3所獲得之化合物(4.7g)、1mol/L氫氧化鈉水溶液(35mL)及甲醇(300mL),與實施例60相同方式製得標題化合物(2.8g,65%)呈晶體。
由實施例4所獲得之化合物(4.5g)、1mol/L氫氧化鈉水溶液(33mL)及甲醇(300mL),與實施例60相同方式製得標題化合物(3.7g,90%)呈晶體。
於實施例5所獲得之化合物(7.1g)之甲醇(290mL)溶液中,於室溫加入1mol/L之氫氧化鈉水溶液(29mL)。將其直接攪拌混合29小時後,於減壓下蒸餾去除溶媒所得之殘質中加入水。以稀鹽酸使成酸性後,濾取析出之晶體而製得標題化合物(5.4g,79%)。
由實施例6所獲得之化合物(4.2g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例60相同方式製得標題化合物(3.7g,86%)呈非晶形固體。
由實施例7所獲得之化合物(3.0g)、1mol/L氫氧化鈉水溶液(35mL)及甲醇(150mL),與實施例60相同方式製得標題化合物(3.0g,98%)呈晶體。
由實施例8所獲得之化合物(3.7g)、1mol/L氫氧化鈉水溶液(32mL)及甲醇(150mL),與實施例60相同方式製得標題化合物(43.7g,98%)呈晶體。
由實施例9所獲得之化合物(5.8g)、1mol/L氫氧化鈉水溶液(23mL)及甲醇(200mL),與實施例60相同方式製得標題化合物(4.3g,73%)呈晶體。
由實施例10所獲得之化合物(3.4g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例60相同方式製得標題化合物(1.6g,46%)呈晶體。
由實施例11所獲得之化合物(5.2g)、1mol/L氫氧化鈉水溶液(42mL)及甲醇(150mL),與實施例60相同方式製得標題化合物(2.9g,55%)呈晶體。
由實施例12所獲得之化合物(4.5g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例64相同方式製得標題化合物(3.7g,85%)呈晶體。
由實施例13所獲得之化合物(3.9g)、1mol/L氫氧化鈉水溶液(15mL)及甲醇(150mL),與實施例60相同方式製得標題化合物(2.7g,68%)呈非晶形固體。
由實施例14所獲得之化合物(4.5g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例60相同方式製得標題化合物(4.1g,89%)呈非晶形固體。
由實施例15所獲得之化合物(4.1g)、1mol/L氫氧化鈉水溶液(16mL)及甲醇(160mL),與實施例64相同方式製得標題化合物(3.9g,99%)呈晶體。
由實施例16所獲得之化合物(2.6g)、1mol/L氫氧化鈉水溶液(8.0mL)及甲醇(80mL),與實施例64相同方式製得標題化合物(2.1g,83%)呈晶體。
由實施例17所獲得之化合物(4.9g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例64相同方式製得標題化合物(4.2g,89%)呈晶體。
由實施例18所獲得之化合物(5.6g)、1mol/L氫氧化鈉水溶液(23mL)及甲醇(230mL),與實施例64相同方式製得標題化合物(3.7g,69%)呈晶體。
由實施例19所獲得之化合物(2.0g)、1mol/L氫氧化鈉水溶液(7.7mL)及甲醇(80mL),與實施例64相同方式製得標題化合物(1.9g,99%)呈晶體。
由實施例21所獲得之化合物(3.9g)、1mol/L氫氧化鈉水溶液(328mL)及甲醇(140mL),與實施例64相同方式製得標題化合物(2.1g,62%)呈晶體。
由實施例22所獲得之化合物(3.1g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例64相同方式製得標題化合物(2.5g,85%)呈晶體。
由實施例23所獲得之化合物(2.7g)、1mol/L氫氧化鈉水溶液(10.5mL)及甲醇(110mL),與實施例64相同方式製得標題化合物(2.1g,80%)呈晶體。
由實施例24所獲得之化合物(1.1g)、1mol/L氫氧化鈉水溶液(4.0mL)及甲醇(40mL),與實施例64相同方式製得標題化合物(0.76g,74%)呈晶體。
由實施例25所獲得之化合物(0.73g)、1mol/L氫氧化鈉水溶液(2.7mL)及甲醇(27mL),與實施例64相同方式製得標題化合物(0.54g,77%)呈晶體。
由實施例26所獲得之化合物(2.9g)、1mol/L氫氧化鈉水溶液(15.0mL)及甲醇(150mL),與實施例64相同方式製得標題化合物(2.1g,74%)呈晶體。
由實施例27所獲得之化合物(0.93g)、1mol/L氫氧化鈉水溶液(3.1mL)及甲醇(30mL),與實施例64相同方式製得標題化合物(0.81g,90%)呈晶體。
由實施例30所獲得之化合物(4.8g)、1mol/L氫氧化鈉水溶液(16mL)及甲醇(160mL),與實施例64相同方式製得標題化合物(3.5g,75%)呈晶體。
由實施例31所獲得之化合物(3.1g)、1mol/L氫氧化鈉水溶液(13mL)及甲醇(130mL),與實施例64相同方式製得標題化合物(2.8g,95%)呈晶體。
由實施例34所獲得之化合物(1.9g)、1mol/L氫氧化鈉水溶液(11mL)及甲醇(70mL),與實施例60相同方式製得標題化合物(1.9g,97%)呈晶體。
由實施例35所獲得之化合物(6.0g)、1mol/L氫氧化鈉水溶液(38mL)及甲醇(300mL),與實施例64相同方式製得標題化合物(4.4g,85%)呈非晶形固體。
實施例36所獲得之化合物(3.1g)之甲醇(240mL)溶液中,於室溫滴下1mol/L氫氧化鈉水溶液(24mL),將其直接攪拌混合17小時。於減壓下蒸餾去除溶媒所得之殘質中加入水,以稀鹽酸使成酸性後,以醋酸乙酯萃取。有機層以飽和食鹽水洗滌後,以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒製得標題化合物(1.4g,51%)呈非晶形固體。
由實施例37所獲得之化合物(2.5g)、1mol/L氫氧化鈉水溶液(19mL)及甲醇(190mL),與實施例90相同方式製得標題化合物(1.2g,57%)呈非晶形固體。
由實施例38所獲得之化合物(5.8g)、1mol/L氫氧化鈉水溶液(24mL)及甲醇(200mL),與實施例90相同方式製得標題化合物(4.2g,76%)呈晶體。
由實施例39所獲得之化合物(2.9g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例90相同方式製得標題化合物(1.7g,61%)呈晶體。
由實施例40所獲得之化合物(2.5g)、1mol/L氫氧化鈉水溶液(21mL)及甲醇(150mL),與實施例90相同方式製得標題化合物(2.2g,90%)呈晶體。
由實施例41所獲得之化合物(3.4g)、1mol/L氫氧化鈉水溶液(19mL)及甲醇(150mL),與實施例90相同方式製得標題化合物(2.0g,62%)呈晶體。
由實施例42所獲得之化合物(3.1g)、1mol/L氫氧化鈉水溶液(13mL)及甲醇(130mL),與實施例64相同方式製得標題化合物(2.7g,89%)呈晶體。
由實施例43所獲得之化合物(4.1g)、1mol/L氫氧化鈉水溶液(15mL)及甲醇(150mL),與實施例64相同方式製得標題化合物(3.3g,83%)呈非晶形固體。
由實施例44所獲得之化合物(1.6g)、1mol/L氫氧化鈉水溶液(13mL)及甲醇(150mL),與實施例90相同方式製得標題化合物(1.2g,75%)呈晶體。
由實施例45所獲得之化合物(2.9g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例64相同方式製得標題化合物(2.4g,79%)呈晶體。
由實施例46所獲得之化合物(3.0g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例64相同方式製得標題化合物(2.8g,95%)呈晶體。
由實施例47所獲得之化合物(2.9g)、1mol/L氫氧化鈉水溶液(12mL)及甲醇(120mL),與實施例64相同方式製得標題化合物(2.7g,96%)呈晶體。
由實施例48所獲得之化合物(2.8g)、1mol/L氫氧化鈉水溶液(11mL)及甲醇(110mL),與實施例64相同方式製得標題化合物(2.4g,89%)呈晶體。
由實施例49所獲得之化合物(3.4g)、1mol/L氫氧化鈉水溶液(11mL)及甲醇(110mL),與實施例90相同方式製得標題化合物(2.3g,71%)呈晶體。
由實施例50所獲得之化合物(3.2g)、1mol/L氫氧化鈉水溶液(11mL)及甲醇(110mL),與實施例64相同方式製得標題化合物(3.1g,99%)呈晶體。
由實施例51所獲得之化合物(3.4g)、1mol/L氫氧化鈉水溶液(15mL)及甲醇(150mL),與實施例64相同方式製得標題化合物(2.6g,78%)呈晶體。
由實施例52所獲得之化合物(2.7g)、1mol/L氫氧化鈉水溶液(11mL)及甲醇(110mL),與實施例90相同方式製得標題化合物(2.1g,80%)呈晶體。
由實施例53所獲得之化合物(4.0g)、1mol/L氫氧化鈉水溶液(21mL)及甲醇(200mL),與實施例64相同方式製得標題化合物(3.6g,93%)呈非晶形固體。
由實施例54所獲得之化合物(4.2g)、1mol/L氫氧化鈉水溶液(39mL)及甲醇(390mL),與實施例64相同方式製得標題化合物(2.9g,73%)呈晶體。
由實施例55所獲得之化合物(3.7g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例64相同方式製得標題化合物(3.0g,85%)呈晶體。
由實施例56所獲得之化合物(4.0g)、1mol/L氫氧化鈉水溶液(34mL)及甲醇(150mL),與實施例60相同方式製得標題化合物(2.4g,62%)呈晶體。
實施例57所獲得之化合物(6.9g)之甲醇(260mL)中,於室溫滴下1mol/L氫氧化鈉水溶液(26mL),將其直接攪拌混合21小時。於減壓下蒸餾去除溶媒所得之殘質中加水,以10%檸檬酸使成酸性。以醋酸乙酯萃取後,有機層以飽和食鹽水洗滌,以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒而獲得標題化合物(5.4g,81%)呈油狀物。
由實施例111所獲得之化合物(5.4g)、4mol/L氯化氫-二烷(11mL)及二氯甲烷(200mL),與實施例29相同方式製得標題化合物(4.1g,90%)呈晶體。
由實施例58所獲得之化合物(4.0g)、1mol/L氫氧化鈉水溶液(186L)及甲醇(160mL),與實施例111相同方式製得標題化合物(3.8g,98%)呈油狀物。
由實施例113所獲得之化合物(3.8g)、4mol/L氯化氫-二烷(7.0mL)及二氯甲烷(80mL),與實施例29相同方式製得標題化合物(3.0g,92%)呈晶體。
由實施例59所獲得之化合物(3.2g)、1mol/L氫氧化鈉水溶液(8.0mL)及甲醇(80mL),與實施例111相同方式製得標題化合物(2.8g,91%)呈油狀物。
實施例115所獲得之化合物(2.8g)之二氯甲烷溶液中,於室溫滴下三氟醋酸,將其直接攪拌混合24小時。於減壓下蒸餾去除溶媒之殘質中加入二乙基醚,於室溫攪拌混合24小時。濾取析出之晶體獲得標題化合物(1.4g,68%)。
3-氰基桂皮酸(9.0g)及N-羥基琥珀醯亞胺(9.0g)之二氯甲烷(300mL)懸浮液中,於0℃加入WSC‧HCl(15.0g)後,於室溫攪拌混合6小時。反應混合物以水洗滌後,有機層以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒所獲得之晶體,以二乙基醚濾取而製得標題化合物(13.0g,93%)。
由4-氰基桂皮酸(5.0g)、N-羥基琥珀醯亞胺(5.0g)、WSC‧HCl(8.3g)及二氯甲烷(150mL),與實施例117相同方式製得標題化合物(6.2g,79%)呈晶體。
α-氰基桂皮酸(10.0g)及N-羥基琥珀醯亞胺(10.0g)之二氯甲烷(300mL)懸浮液中,於0℃加入WSC‧HCl(16.6g)後,於室溫攪拌混合22小時。反應混合物以水洗滌後,有機層以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒所獲得之殘質以矽膠管柱層析(氯仿)精製,製得標題化合物(6.9g,44%)呈晶體。
由α-氰基-2-氟桂皮酸(12.0g)、N-羥基琥珀醯亞胺(10.8g)、WSC‧HCl(18.1g)及二氯甲烷(300mL),與實施例119相同方式製得標題化合物(8.0g,44%)呈晶體。
L-色胺酸(3.0g)之水(80mL)-二烷(80mL)溶液中,於0℃加入碳酸氫鈉(1.3g),於室溫攪拌混合30分鐘。其次,於0℃加入實施例117所獲得之化合物(4.2g)之二烷(80mL)溶液,於室溫攪拌混合17小時。減壓下濃縮反應混合物至1/3容積後,以10%檸檬酸水溶液使成酸性後,濾取析出之晶體。晶體以水洗滌而獲得標題化合物(4.6g,87%)。
由L-色胺酸(2.0g)、碳酸氫鈉(0.9g)、實施例118所獲得之化合物(3.3g)、水(70mL)及二烷(160mL),與實施例121相同方式製得標題化合物(1.9g,53%)呈晶體。
由L-色胺酸(2.5g)、碳酸氫鈉(1.1g)、實施例119所獲得之化合物(3.3g)、水(70mL)及二烷(150mL),與實施例121相同方式製得標題化合物(1.3g,29%)呈晶體。
由L-色胺酸(3.0g)、碳酸氫鈉(1.3g)、實施例120所獲得之化合物(4.2g)、水(80mL)及二烷(160mL),與實施例121相同方式製得標題化合物(2.5g,45%)呈晶體。
Nα
-苯甲氧基羰基-L-色胺酸-2,5-二酮基吡咯啶-1-基酯(5.0g)之THF(150mL)之溶液中,於0℃滴下30%氨水(3.3mL)後,於室溫攪拌混合2小時。濾除了晶體後,於減壓下蒸餾去除濾液之溶媒所得之殘質中,加入石油醚及少量的二乙基醚,濾取析出之晶體獲得標題化合物(3.6g,91%)。
實施例125所獲得之化合物(3.6g)之甲醇(300mL)溶液中,於氬氛圍下加入5%鈀/碳(0.36g)後,氫氛圍中,於室溫攪拌混合16小時。濾除了觸媒,於減壓下蒸餾去除溶媒而獲得標題化合物(2.1g,95%)呈油狀物。
3-(2-氟苯基)丙烯酸2,5-二酮基吡咯啶-1-基酯(2.7g)之THF(80mL)溶液中,於0℃滴下化合物128(2.1g)之THF(80mL)懸浮液後,於室溫攪拌混合2小時。加入DMF(10mL)後,再於室溫攪拌混合19小時。於減壓下蒸餾去除溶媒所得之殘質中加入醋酸乙酯,水洗滌後,有機層以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒所得之殘質,以矽膠管柱層析(BW-127ZH,氯仿:甲醇=40:1)精製,製得標題化合物(1.6g,43%)呈晶體。
由1-甲基-L-色胺酸(2.0g)、碳酸氫鈉(0.8g)、3-苯基丙烯酸2,5-二酮基吡咯啶-1-基酯(2.3g)、水(60mL)及二烷(140mL),與實施例121相同方式製得標題化合物(1.1g,33%)呈晶體。
1-甲基-L-色胺酸(2.1g)之水(60mL)-二烷(60mL)懸浮液中,於0℃加入碳酸氫鈉(0.8g),於室溫攪拌混合30分鐘。於0℃滴下3-(2-氰基苯基)丙烯酸2,5-二酮基吡咯啶-1-基酯(2.5g,9.2mmol)之二烷(80mL)溶液,於室溫攪拌混合15小時。減壓下濃縮反應混合物至1/3容積後,加入水,以二乙基醚洗滌。水層以10%檸檬酸水溶液使成酸性後,以醋酸乙酯萃取。有機層以飽和食鹽水洗滌後。以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒而獲得標題化合物(0.96g,27%)呈非晶形固體。
由1-甲基-L-色胺酸(2.0g)、碳酸氫鈉(0.8g)、實施例117獲得之化合物(2.5g)、水(60mL)及二烷(140mL),與實施例121相同方式製得標題化合物(3.1g,90%)呈晶體。
由1-甲基-L-色胺酸(2.1g)、碳酸氫鈉(0.8g)、實施例118獲得之化合物(2.5g)、水(60mL)及二烷(140mL),與實施例129相同方式製得標題化合物(1.8g,53%)呈非晶形固體。
1-甲基-L-色胺酸(2.1g)之水(60mL)-二烷(60mL)懸浮液中,於0℃加入碳酸氫鈉(0.8g),於室溫攪拌混合30分鐘。於0℃滴下實施例120所獲得之化合物(2.6g,9.2mmol)之二烷(80mL)溶液,於室溫攪拌混合21小時。減壓下濃縮反應混合物至1/3容積後,加入水,以二乙基醚洗滌。水層以10%檸檬酸水溶液使成酸性後,以醋酸乙酯萃取。有機層以飽和食鹽水洗滌後。以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒之殘質,以矽膠管柱層析(BW-127ZH,氯仿:甲醇=50:1)精製,製得標題化合物(0.6g,17%)呈非晶形固體。
由O4
-甲基-L-酪胺酸(2.0g)、碳酸氫鈉(0.9g)、實施例117獲得之化合物(2.8g)、水(60mL)及二烷(160mL),與實施例129相同方式製得標題化合物(1.8g,50%)呈非晶形固體。
由O4
-甲基-L-酪胺酸(2.0g)、碳酸氫鈉(0.9g)、實施例118獲得之化合物(2.8g)、水(60mL)及二烷(160mL),與實施例121相同方式製得標題化合物(1.6g,43%)呈晶體。
由L-麩胺酸(2.0g)、3-(2-氟苯基)丙烯酸2,5-二酮基吡咯啶-1-基酯(3.6g)、碳酸氫鈉(1.2g)、水(60mL)及二烷(160mL),與實施例129相同方式製得標題化合物(2.3g,58%)呈晶體。
由L-酪胺酸(2.0g)、3-(2-氟苯基)丙烯酸2,5-二酮基吡咯啶-1-基酯(4.6g)、碳酸氫鈉(1.5g)、水(80mL)及二烷(80mL),與實施例132相同方式製得標題化合物(2.2g,41%)呈晶體。
氫氧化鈉(4.6g)於氬氛圍下微粉末化後,加入二氯甲烷(160mL)、Nα
-第三丁氧基羰基-L-色胺酸(10.0g)、碘乙烷(13.2mL)及四-正丁基硫酸氫銨(1.1g),於室溫攪拌混合64小時。反應混合物以10%檸檬酸水溶液及飽和食鹽水洗滌後,有機層以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒所得之殘質以矽膠管柱層析(氯仿:甲醇=200:1)精製,製得標題化合物(5.7g,52%)呈油狀物。
由氫氧化鈉(2.8g)、二氯甲烷(100mL)、Nα
-第三丁氧基羰基-L-色胺酸(6.0g)、2-碘丙烷(9.8mL)及4-正丁基硫酸氫銨(0.7g),與實施例137相同方式製得標題化合物(1.6g,23%)呈油狀物。
由氫氧化鈉(4.6g)、二氯甲烷(160mL)、Nα
-第三丁氧基羰基-L-色胺酸(6.0g)、1-碘丁烷(19mL)及4-正丁基硫酸氫銨(1.1g),與實施例137相同方式製得標題化合物(6.2g,52%)呈油狀物。
實施例137所獲得之化合物(5.7g)之DMF(80mL)溶液中,於0℃加入碳酸鉀(3.6g)及碘甲烷(1.6mL),於室溫攪拌混合17小時。反應混合物注入至冰水中,以醋酸乙酯萃取。有機層以無水硫酸鈉乾燥後,於減壓下蒸餾去除溶媒所得之殘質以矽膠管柱層析(正己烷:醋酸乙酯=5:1)精製,製得標題化合物(4.8g,81%)呈油狀物。
由實施例138所獲得之化合物(1.6g)、碳酸鉀(0.94g)、碘甲烷(0.42mL)及DMF(40mL),與實施例140相同方式製得標題化合物(1.4g,86%)呈油狀物。
由實施例139所獲得之化合物(6.2g)、碳酸鉀(3.6g)、碘甲烷(1.6mL)及DMF(100mL),與實施例140相同方式製得標題化合物(4.2g,65%)呈油狀物。
實施例140所獲得之化合物(4.8g)之二氯甲烷(175mL)溶液中,於室溫滴下4mol/L氯化氫-二烷溶液(17.5mL),將其直接攪拌混合17小時。濾取析出晶體,以二乙基醚洗滌而獲得標題化合物(2.9g,74%)。
由實施例141所獲得之化合物(1.4g)、4mol/L氯化氫-二烷溶液(4.8mL)及二氯甲烷(50mL),與實施例143相同方式製得標題化合物(0.75g,66%)呈晶體。
由實施例142所獲得之化合物(4.2g)、4mol/L氯化氫-二烷溶液(14.0mL)及二氯甲烷(140mL),與實施例143相同方式製得標題化合物(2.2g,63%)呈晶體。
實施例143所獲得之化合物(2.8g)之二氯甲烷(70mL)懸浮液中,於0℃加入三乙基胺(1.5mL)、1-氟桂皮酸(1.8g)及WSC‧HCl(2.1g),於室溫攪拌混合4小時。反應混合物以水洗滌後,有機層以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒所得之殘質以矽膠管柱層析(氯仿)精製,製得標題化合物(2.7g,70%)呈晶體。
由實施例144所獲得之化合物(0.7g)、三乙基胺(0.4mL)、2-氟桂皮酸(0.44g)、WSC‧HCl(0.50g)及二氯甲烷(20mL),與實施例146相同方式製得標題化合物(0.9g,98%)呈油狀物。
由實施例145所獲得之化合物(2.0g)、三乙基胺(1.0mL)、2-氟桂皮酸(1.2g)、WSC‧HCl(1.4g)及二氯甲烷(60mL),與實施例146相同方式製得標題化合物(2.1g,77%)呈油狀物。
實施例146所獲得之化合物(2.6g)之甲醇(100mL)溶液中,於室溫滴下1mol/L氫氧化鈉水溶液(9.9mL),將其直接攪拌混合23小時。濃縮反應混合物至1/5容積後,加入水以稀鹽酸使成酸性。濾取析出之晶體,以水洗滌而獲得標題化合物(2.3g,93%)。
由實施例147所獲得之化合物(0.98g)、1mol/L氫氧化鈉水溶液(3.6mL)及甲醇(40mL),與實施例149相同方式製得標題化合物(0.67g,71%)呈晶體。
由實施例148所獲得之化合物(2.1g)、1mol/L氫氧化鈉水溶液(7.5mL)及甲醇(75mL),與實施例149相同方式製得標題化合物(1.8g,87%)呈晶體。
由氫氧化鈉(4.6g)、二氯甲烷(160mL)、Nα
-第三丁氧基羰基-L-色胺酸(10.0g)、苯甲基溴(20mL)及四正丁基硫酸氫銨(1.1g),與實施例137相同方式製得標題化合物(12.2g,77%)呈油狀物。
由實施例152所獲得之化合物(12.2g)、4mol/L氯化氫-二烷溶液(31mL)及二氯甲烷(300mL),與實施例143相同方式製得標題化合物(8.6g,81%)呈晶體。
由實施例153所獲得之化合物(1.0g)、三乙基胺(0.4mL)、2-氟桂皮酸(0.43g)、WSC‧HCl(0.50g)及二氯甲烷(50mL),與實施例146相同方式製得標題化合物(0.97g,77%)呈油狀物。
由實施例154所獲得之化合物(0.97g)、1mol/L氫氧化鈉水溶液(2.7mL)及甲醇(27mL),與實施例149相同方式製得標題化合物(0.57g,71%)呈晶體。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、2-甲基桂皮酸(2.3g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.2g,98%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、3-甲基桂皮酸(2.3g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.2g,98%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、4-甲基桂皮酸(2.3g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.3g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、4-正丁基桂皮酸(2.9g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.8g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、4-異丙基桂皮酸(2.7g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.5g,98%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(4.0g)、三乙基胺(2.6mL)、巴豆酸(1.6g)、WSC‧HCl(3.6g)及二氯甲烷(110mL),與實施例146相同方式製得標題化合物(4.4g,98%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、3-甲基巴豆酸(1.4g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(2.7g,77%)呈晶體。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、惕各酸(1.4g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(3.5g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、反式-2-己烯酸(1.6g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(3.7g,99%)呈油狀物。
由L-色胺酸甲基酯鹽酸鹽(3.0g)、三乙基胺(2.0mL)、α-甲基桂皮酸(2.3g)、WSC‧HCl(2.7g)及二氯甲烷(80mL),與實施例146相同方式製得標題化合物(4.0g,94%)呈油狀物。
由實施例156所獲得之化合物(4.2g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例149相同方式製得標題化合物(3.6g,88%)呈晶體。
由實施例157所獲得之化合物(4.2g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例149相同方式製得標題化合物(3.7g,92%)呈晶體。
由實施例158所獲得之化合物(4.3g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例149相同方式製得標題化合物(3.7g,89%)呈晶體。
由實施例159所獲得之化合物(4.8g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例149相同方式製得標題化合物(4.0g,87%)呈晶體。
由實施例160所獲得之化合物(4.5g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例149相同方式製得標題化合物(3.8g,87%)呈晶體。
實施例161所獲得之化合物(4.4g)之甲醇(230mL)溶液中,加入1mol/L氫氧化鈉水溶液(23mL),將其直接攪拌混合20小時。於減壓下蒸餾去除溶媒所得之殘質中加入水,以10%檸檬酸水溶液使成酸性。反應混合物以醋酸乙酯萃取,有機層以飽和食鹽水洗滌後,以無水硫酸鈉乾燥。於減壓下蒸餾去除溶媒,製得標題化合物(3.0g,71%)呈非晶形固體。
由實施例162所獲得之化合物(2.5g)、1mol/L氫氧化鈉水溶液(13mL)及甲醇(130mL),與實施例171相同方式製得標題化合物(1.9g,78%)呈非晶形固體。
由實施例163所獲得之化合物(3.5g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例171相同方式製得標題化合物(2.3g,70%)呈非晶形固體。
由實施例164所獲得之化合物(3.7g)、1mol/L氫氧化鈉水溶液(18mL)及甲醇(180mL),與實施例171相同方式製得標題化合物(2.1g,58%)呈非晶形固體。
由實施例165所獲得之化合物(4.0g)、1mol/L氫氧化鈉水溶液(17mL)及甲醇(170mL),與實施例149相同方式製得標題化合物(3.4g,89%)呈晶體。
上述製造所得之本發明化合物之物性數據示於表1至表10。
本發明化合物經口投予至小鼠,藉由醋酸扭體實驗(acetic acid writhing test)進行鎮痛效力試驗(侵害接受性疼痛模式動物)。預備飼養4週齡之雄性ddY系小鼠作為實驗動物,實驗中使用8隻小鼠為1群。將本發明化合物溶解或懸浮於0.5%(w/v)CMC-Na水溶液中作為被驗物質而單次經口投予,再者,對照群為同樣地投予0.5%(w/v)CMC-Na水溶液。投予25分鐘後,以10mL/kg腹腔內投予0.7%(v/v)醋酸/生理食鹽液,於投予後5分鐘至10分鐘期間計測扭體次數,根據下述式而算出各個體之抑制率(平均值±標準誤差)。
抑制率(%)=(對照群之平均扭體次數-各個體之扭體次數)÷對照群之平均扭體次數×100
又,顯著差異的檢定,對照群與被驗物質投予群之多群間的比較係進行Baltlett檢定,等分散時使用參數的Dunnett多重檢定比較,不等分散時使用無參數的Dunnett多重檢定比較。再者,用量依存性的檢定係使用Jockheere-Terpstra檢定。任一情況中皆以P<0.05作為顯著差異。
上述試驗結果之一例示於表11及表12。藉由醋酸扭體法進行鎮痛效力試驗的結果,本發明化合物顯示優異之鎮痛效果。
使用神經因性疼痛模式動物之Chung模式大鼠,進行鎮痛效力試驗。使用超過9週齡之Wistar系雄性大鼠作為實驗動物,以Kim與Chung的方法(Pain,50卷,355-363頁,1992年)為基準,製作模式大鼠。亦即,於戊巴比妥(35mg/kg,腹腔內投予)麻醉下,將大鼠左L5脊髓神經曝露且以5-0絹絲強力地結紮L5後根神經節末梢側。將動物放入底部為金屬網所成之透明壓克力籠。使用von Frey細絲(North Coast Medical Inc.製造),根據Chaplan等人(J. Neurosci. Method,53卷,55-63頁,1994年)及Lee等人(J. Neurophysiol.,81卷,2226-2233頁,1999年)之方法,藉由up-down法算出50%反應閾值,實施激烈疼痛(allodynia)的測定。50%反應閾值係於脊髓神經損傷前測定2次,閾值為基準外的動物則由脊髓神經損傷手術排除了。脊髓神經損傷14日後開始測定50%反應閾值,以顯示閾值為1g以上且未達4g者作為實驗用動物,以各群之50%反應閾值的平均值幾乎一致的方式,構成1群7隻動物。
將本發明化合物溶解或懸浮於0.5%(w/v)CMC-Na水溶液中作為被驗物質而單次經口投予,再者,神經損傷對照群為同樣地投予0.5%(w/v)CMC-Na水溶液。投予30分鐘後,進行激烈疼痛的測定,算出50%反應閾值(平均值±標準誤差)。又,顯著差異的檢定,神經損傷對照群與被驗物質投予群之多群間的比較係進行Baltlett檢定,等分散時使用參數的Dunnett多重檢定比較,不等分散時使用無參數的Dunnett多重檢定比較。再者,用量依存性的檢定係使用Jockheere-Terpstra檢定。任一情況中皆以P<0.05作為顯著差異。
試驗結果之一例示於表13及表14。使用神經因性疼痛模式之Chung模式大鼠進行鎮痛效力試驗的結果,本發明化合物顯示顯著優異之鎮痛效果。
將本發明化合物10mg,必要時以等量的氫氧化鈉作為適宜的鈉鹽,分別溶解於5mL水中。將該等本發明化合物每5個化合物混合,而調製含各化合物各為0.4mg/mL之混合溶液,使用鼻餵管(sonde)單次經口投予至經禁食之6週齡Wistar系SPF雄性大鼠(各化合物2mg/5mL/kg,n=5)。投予後,於0.25、0.5、1、2、4、8小時的時間點,使用添加有肝素之毛細管由尾靜脈採血約150μL,將該毛細管離心分離而採得血漿。將血漿樣品去除了蛋白後,稀釋上清液而調製各測定樣品液。使用LC-MS對各測定樣品液定量本發明化合物的濃度,算出本發明化合物之Cmax(最高血漿中濃度)及AUC(血中濃度曲線下面積,0-∞小時)。
上述試驗結果之一例示於表15。本發明化合物於Cmax及AUC均顯示高的值,確認經口投予時之大鼠血中移動性優異。
如上述各種鎮痛效果試驗所示,本發明之胺基酸衍生物為不僅對侵害接受性疼痛模式動物顯示鎮痛作用,對於神經因性疼痛模式動物亦顯示優異之鎮痛作用,且為經口投子時具有優異之血中移動性之化合物。因此,本發明化合物非常有用於做為各種急性或慢性疼痛疾患,或非類固醇性消炎鎮痛藥(NSAIDs)等鎮痛藥難有效果之反射性交感神經性萎縮(dystrophy)、帶狀疱疹後神經痛、糖尿病性神經病變等神經因性疼痛疾患等治療用之藥劑。
Claims (30)
- 一種胺基酸衍生物或者其藥學上容許之鹽或水合物,該胺基酸衍生物係如下述通式(I)所示
- 如申請專利範圍第1項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R5 為羥基。
- 如申請專利範圍第2項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R2 為氫。
- 如申請專利範圍第3項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R1 為吲哚。
- 如申請專利範圍第4項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氰基取代之苯基。
- 如申請專利範圍第4項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氟取代之苯基。
- 如申請專利範圍第4項之胺基酸衍生物或者其藥學上 容許之鹽或水合物,其中,R4 為經苯氧基取代之苯基。
- 如申請專利範圍第3項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R1 為經碳數1至6之烷基於N位取代之吲哚。
- 如申請專利範圍第8項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氰基取代之苯基。
- 如申請專利範圍第8項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氟取代之苯基。
- 如申請專利範圍第8項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經苯氧基取代之苯基。
- 如申請專利範圍第3項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R1 為經碳數1至4之烷氧基取代之苯基。
- 如申請專利範圍第12項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氰基取代之苯基。
- 如申請專利範圍第12項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R4 為經氟取代之苯基。
- 如申請專利範圍第3項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R1 為經胺基或胍基取代之碳數1至6之烷基。
- 如申請專利範圍第3項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R1 為羥基。
- 如申請專利範圍第2項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R2 為氰基。
- 如申請專利範圍第1項之胺基酸衍生物或者其藥學上容許之鹽或水合物,其中,R5 為胺基,R2 為氫。
- 一種Nα -[3-(2-氟苯基)丙烯醯基]-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種Nα -[3-(3-氰基苯基)丙烯醯基]-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種Nα -[2-氰基-3-(2-氟苯基)丙烯醯基]-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種Nα -[3-(2-氟苯基)丙烯醯基]-1-甲基-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種Nα -[3-(4-氰基苯基)丙烯醯基]-1-甲基-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種Nα -[2-氰基-3-(2-氟苯基)丙烯醯基]-1-甲基-L-色胺酸或者其藥學上容許之鹽或水合物。
- 一種醫藥,含有下述通式(I’)所示之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分
- 如申請專利範圍第25項之醫藥,其係含有R1 ’為吲哚之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分。
- 如申請專利範圍第26項之醫藥,其係含有R4 ’為經氰基或氟取代之苯基之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分。
- 如申請專利範圍第25項之醫藥,其係含有R1 ’為經碳數1至6之烷基於N位取代之吲哚之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分。
- 如申請專利範圍第28項之醫藥,其係含有R4 ’為經氰基或氟取代之苯基之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分。
- 一種鎮痛藥,含有下述通式(I”)所示之胺基酸衍生物或者其藥學上容許之鹽或水合物作為有效成分
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